Sex-specific Epigenetic Disruption and Behavioral Changes Following Low-dose in Utero Bisphenol A Exposure

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2013 May 30

PMID 23716699

Citations 214

Authors

Marija Kundakovic

Kathryn Gudsnuk

Becca Franks

Jesus Madrid

Rachel L Miller

Frederica P Perera

Frances A Champagne

Affiliations

Soon will be listed here.

Abstract

Bisphenol A (BPA) is an estrogenic endocrine disruptor widely used in the production of plastics. Increasing evidence indicates that in utero BPA exposure affects sexual differentiation and behavior; however, the mechanisms underlying these effects are unknown. We hypothesized that BPA may disrupt epigenetic programming of gene expression in the brain. Here, we provide evidence that maternal exposure during pregnancy to environmentally relevant doses of BPA (2, 20, and 200 µg/kg/d) in mice induces sex-specific, dose-dependent (linear and curvilinear), and brain region-specific changes in expression of genes encoding estrogen receptors (ERs; ERα and ERβ) and estrogen-related receptor-γ in juvenile offspring. Concomitantly, BPA altered mRNA levels of epigenetic regulators DNA methyltransferase (DNMT) 1 and DNMT3A in the juvenile cortex and hypothalamus, paralleling changes in estrogen-related receptors. Importantly, changes in ERα and DNMT expression in the cortex (males) and hypothalamus (females) were associated with DNA methylation changes in the ERα gene. BPA exposure induced persistent, largely sex-specific effects on social and anxiety-like behavior, leading to disruption of sexually dimorphic behaviors. Although postnatal maternal care was altered in mothers treated with BPA during pregnancy, the effects of in utero BPA were not found to be mediated by maternal care. However, our data suggest that increased maternal care may partially attenuate the effects of in utero BPA on DNA methylation. Overall, we demonstrate that low-dose prenatal BPA exposure induces lasting epigenetic disruption in the brain that possibly underlie enduring effects of BPA on brain function and behavior, especially regarding sexually dimorphic phenotypes.

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References

US Environmental Protection Agency . Issuance of experimental use permits; genetically engineered microbial pesticides; Advanced Genetic Sciences, Inc.; notice. Fed Regist. 1985; 50(233):49760-2. View

Perera F, Vishnevetsky J, Herbstman J, Calafat A, Xiong W, Rauh V . Prenatal bisphenol a exposure and child behavior in an inner-city cohort. Environ Health Perspect. 2012; 120(8):1190-4. PMC: 3440080. DOI: 10.1289/ehp.1104492. View

Vandenberg L, Maffini M, Sonnenschein C, Rubin B, Soto A . Bisphenol-A and the great divide: a review of controversies in the field of endocrine disruption. Endocr Rev. 2008; 30(1):75-95. PMC: 2647705. DOI: 10.1210/er.2008-0021. View

Bromer J, Zhou Y, Taylor M, Doherty L, Taylor H . Bisphenol-A exposure in utero leads to epigenetic alterations in the developmental programming of uterine estrogen response. FASEB J. 2010; 24(7):2273-80. PMC: 3230522. DOI: 10.1096/fj.09-140533. View

Reik W . Stability and flexibility of epigenetic gene regulation in mammalian development. Nature. 2007; 447(7143):425-32. DOI: 10.1038/nature05918. View

LaPlant Q, Vialou V, Covington 3rd H, Dumitriu D, Feng J, Warren B . Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens. Nat Neurosci. 2010; 13(9):1137-43. PMC: 2928863. DOI: 10.1038/nn.2619. View

Feng J, Chang H, Li E, Fan G . Dynamic expression of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the central nervous system. J Neurosci Res. 2005; 79(6):734-46. DOI: 10.1002/jnr.20404. View

Skinner M, Anway M, Savenkova M, Gore A, Crews D . Transgenerational epigenetic programming of the brain transcriptome and anxiety behavior. PLoS One. 2008; 3(11):e3745. PMC: 2581440. DOI: 10.1371/journal.pone.0003745. View

Richter C, Birnbaum L, Farabollini F, Newbold R, Rubin B, Talsness C . In vivo effects of bisphenol A in laboratory rodent studies. Reprod Toxicol. 2007; 24(2):199-224. PMC: 2151845. DOI: 10.1016/j.reprotox.2007.06.004. View

10.

Monje L, Varayoud J, Munoz-de-Toro M, Luque E, Ramos J . Exposure of neonatal female rats to bisphenol A disrupts hypothalamic LHRH pre-mRNA processing and estrogen receptor alpha expression in nuclei controlling estrous cyclicity. Reprod Toxicol. 2010; 30(4):625-34. DOI: 10.1016/j.reprotox.2010.08.004. View

11.

McCarthy M, Arnold A . Reframing sexual differentiation of the brain. Nat Neurosci. 2011; 14(6):677-83. PMC: 3165173. DOI: 10.1038/nn.2834. View

12.

Wetherill Y, Akingbemi B, Kanno J, McLachlan J, Nadal A, Sonnenschein C . In vitro molecular mechanisms of bisphenol A action. Reprod Toxicol. 2007; 24(2):178-98. DOI: 10.1016/j.reprotox.2007.05.010. View

13.

Champagne F, Weaver I, Diorio J, Dymov S, Szyf M, Meaney M . Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring. Endocrinology. 2006; 147(6):2909-15. DOI: 10.1210/en.2005-1119. View

14.

Feng J, Zhou Y, Campbell S, Le T, Li E, Sweatt J . Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci. 2010; 13(4):423-30. PMC: 3060772. DOI: 10.1038/nn.2514. View

15.

Kubo K, Arai O, Omura M, Watanabe R, Ogata R, Aou S . Low dose effects of bisphenol A on sexual differentiation of the brain and behavior in rats. Neurosci Res. 2003; 45(3):345-56. DOI: 10.1016/s0168-0102(02)00251-1. View

16.

Meaney M . Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu Rev Neurosci. 2001; 24:1161-92. DOI: 10.1146/annurev.neuro.24.1.1161. View

17.

Lund T, Rovis T, Chung W, Handa R . Novel actions of estrogen receptor-beta on anxiety-related behaviors. Endocrinology. 2004; 146(2):797-807. DOI: 10.1210/en.2004-1158. View

18.

Patisaul H, Fortino A, Polston E . Neonatal genistein or bisphenol-A exposure alters sexual differentiation of the AVPV. Neurotoxicol Teratol. 2006; 28(1):111-8. DOI: 10.1016/j.ntt.2005.11.004. View

19.

Handa R, Ogawa S, Wang J, Herbison A . Roles for oestrogen receptor β in adult brain function. J Neuroendocrinol. 2011; 24(1):160-73. PMC: 3348521. DOI: 10.1111/j.1365-2826.2011.02206.x. View

20.

Kurian J, Olesen K, Auger A . Sex differences in epigenetic regulation of the estrogen receptor-alpha promoter within the developing preoptic area. Endocrinology. 2010; 151(5):2297-305. PMC: 2869250. DOI: 10.1210/en.2009-0649. View